The present invention relates to a triazine compound which is useful in the treatment of central nervous system (CNS) diseases and disorders and to its pharmaceutically acceptable derivatives, to pharmaceutical compositions containing them, to their use in the treatment of such disorders and to methods of preparation.
EP-A-0021121 and EP-A-0247892 describe 3,5-diamino triazines, for example 3,5diamino-6-(2,3dichlorophenyl)-1,2,4-triazine (lamotrigine), which are active in the treatment of disorders of the CNS and are particularly useful in the treatment of epilepsy.
The present invention relates to a 5-amino triazine derivative which is a sodium channel blocker. This compound is a surprisingly potent anti-convulsant having increased potency with respect to lamotrigine and increased selectivity in terms of CNS side-effects and inhibition of the enzyme dihydrofolate reductase. The compound is therefore useful in the treatment of CNS diseases such as epilepsy.
Accordingly, the invention provides a compound of formula (I) 
i.e. 5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine and pharmaceutically acceptable derivatives thereof.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of the compounds of formula (1), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof (eg. a prodrug). Reference hereinafter to the compounds of formula (I) includes the compound of formula (I) and pharmaceutically acceptable derivatives thereof.
Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
Suitable prodrugs are well-known in the art and include N-acyl derivatives, for example at either of the four nitrogens in the compounds of formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as Rxe2x80x94Oxe2x80x94CH2-nitrogen or Rxe2x80x94Oxe2x80x94C(O)-nitrogen.
The compounds of formula (I) are particularly useful as anticonvulsants. They are therefore useful in treating epilepsy. They may be used to improve the condition of a host, typically a human being, suffering from epilepsy. They may be employed to alleviate the symptoms of epilepsy in a host xe2x80x9cEpilepsyxe2x80x9d is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
The compounds of formula (I) are additionally useful in the treatment of bipolar disorder, alternatively known as manic depression. Type I or II bipolar disorder may be treated. The compounds of formula (I) may thus be used to improve the condition of a human patient suffering from bipolar disorder. They may be used to alleviate the symptoms of bipolar disorder in a host. The compounds of formula (I) may also be used in the treatment of unipolar depression.
The compounds of formula (I) are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compounds of formula (I) may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (eg. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compounds of formula (I) may also be used in the treatment or prevention of pain associated with migraine.
The compounds of formula (I) are further useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterised by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compounds of formula (I) may thus be used to alleviate pain associated with irritable bowel syndrome The condition of a human patient suffering from irritable bowel syndrome may thus be improved.
The compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases, such as Alzheimer""s disease, ALS, motor neuron disease, Parkinson""s disease, muscular sclerosis, macular degeneration and glaucoma. The compounds of formula (I) may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
The compounds of formula (I) are further useful in the treatment of tinnitus.
Still further, the compounds of formula (I) are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence inducing agent. Examples of dependence inducing agents include opioids (eg morphine), CNS depressants (eg ethanol), psychostimulants (eg cocaine) and nicotine.
There is therefore further provided by the present invention, use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human and veterinary medicine.
There is therefore further provided by the present invention, use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of a disorder substantially as hereinbefore described.
The present invention further comprises a method of treating a patient suffering from, or susceptible to, a disorder substantially as hereinbefore described, which method comprises administering to the patient a therapeutically effective amount of a compound of formula (I).
The term xe2x80x9ctreatmentxe2x80x9d as used herein includes the treatment of established disorders, and also includes the prophylaxis thereof
The precise amount of the compounds of formula (I) administered to a host, particularly a human patient, will be the responsibility of the attendant physician However, the dose employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration.
The compound of formula (I) may be administered at a dose of from 0.1 to 10 mg/kg body weight per day and more particularly 0.3 to 3 mg/kg body weight per day, calculated as the free base. The dose range for adult human beings is generally from 8 to 1000 mg/day, such as from 35 to 800 mg/day, preferably 10 to 200 mg/day or 20 to 200 mg/day, calculated as the free base.
The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of formula (I) thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
Preferred unit dosage formulations are those containing an effective daily dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. Conveniently that may be from 5 mg to 1000 mg, such as from 8 mg to 1000 mg, more conveniently 35 mg to 800 mg, and most conveniently 10 to 200 mg or 20 to 200 mg, calculated as the free base.
The compounds of formula (I) may be used in combination with other therapeutic agents, for example other anticonvulsants. When compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof with a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
The present invention provides a process for preparing compounds of formula (I) and pharmaceutically acceptable derivatives thereof.
The compounds of formula (I) may be prepared by the methods outlined below which form a further aspect of the invention.
According to a general process (A), which forms a further aspect of the invention, a compound of formula (I) may be prepared under suitable reaction conditions from a compound of formula (II) 
for example, by reduction, preferably using a reduction metal, such as Raney nickel, and a source of hydrogen, such as hydrazine monohydrate, in a suitable solvent, such as ethanol, preferably at elevated temperature, for example between 70-750xc2x0 C.
According to another process (B), which forms a further aspect of the invention, a compound of formula (I) may be prepared under suitable reaction conditions by reacting a compound of formula (III) 
wherein n may be one or two, with a reducing agent. Suitable reducing agsents include borohydrides, preferably sodium borohydride. The reaction may be carried out in a solvent mixture, such as an ether, preferably tetrahydrofuran and an alcohol, preferably t-butanol and at room temperature.
A compound of formula (III) may be prepared under suitable reaction conditions by reacting a compound of formula (II) with an oxidising agent, such as a peracid, for example potassium peroxymonosulfate or m-chloroperbenzoic acid and at a reduced temperature, for example,  less than 5xc2x0 C. and this forms a further aspect of the invention.
A compound of formula (II) may suitably be prepared by reacting 2,3,5-trichlorobenzoyl cyanide with a S-methylthiosemicarbazide salt, preferably hydroiodide, in the presence of a dilute mineral acid, preferably dilute sulphuric acid and this forms a further aspect of the invention.
A compound of formula (II) may alternatively be prepared under suitable reaction conditions by the photolysis of a solution of a compound of formula (IV), at between 320 and 750 nm 
in a suitable solvent, such as an alcohol, preferably propan-1-ol and at elevated temperature, for example the reflux temperature of the solvent and this forms a further aspect of the invention.
2,3,5-trichlorobenzoyl cyanide and S-methylthiosemicarbazide may be prepared according to conventional procedures and this forms a further aspect of the invention.
A compound of formula (IV) may be prepared under suitable reaction conditions by reacting a compound of formula (V) 
with a dehydrating agent, preferably diphosphoryl chloride and this forms a further aspect of the invention.
A compound of formula (V) may suitably be prepared by the reaction of a compound of formula (VI) 
with a S-methylthiosemicarbazide salt, preferably hydroiodide, in a suitable solvent, for example ethanol, and at elevated temperature, for example 50xc2x0 C. and this forms a further aspect of the invention.
A compound of formula (VI) may be prepared under suitable reaction conditions by reacting 2,3,5-trichlorobenzoyl cyanide with a strong aqueous acid, preferably concentrated hydrochloric acid, which forms a further aspect of the invention.
Prodrugs of the compounds of formula (I) may be prepared according to conventional procedures.